期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 13, 页码 3527-3532出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519389113
关键词
Cul1 affinity; SCF inhibitors; Fbxw7; Fbxw11; beta-Trcp
资金
- Canadian Institutes of Health Research [MOP-136956, MOP-126129]
- Canadian Cancer Society Research Institute
- National Center for Research Resources at the National Institutes of Health [GM103403]
- US Department of Energy, Office of Basic Energy Sciences [DE-AC02-06CH11357]
Skp1-Cul1-F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface. Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies.
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